Stereocontrolled alkylation of chiral pyridinium salt toward a short enantioselective access to 2-alkyl- and 2,6-dialkyl-1,2,5,6-tetrahydropyridines.

Bertin, Bérangère Guilloteau; Compère, Delphine; Gil, Laurent Frédéric; Marazano, Christian; Das, Bhupesh C.

Stereocontrolled alkylation of chiral pyridinium salt toward a short enantioselective access to 2-alkyl- and 2,6-dialkyl-1,2,5,6-tetrahydropyridines.

Date

2000

Authors

Bertin, Bérangère Guilloteau

Compère, Delphine

Gil, Laurent Frédéric

Marazano, Christian

Das, Bhupesh C.

Abstract

Treatment of salts 1a–b with Grignard reagents gives, after reduction of the resulting unstable dihydropyridines 7, the tetrahydropyridines 8a–c, with modest selectivities but in very few steps and under practical conditions. Higher stereoand regioselectivities are obtained with salt 1c which gives the tetrahydropyridines 15a–e. In addition, the dihydropyrid- Introduction The enantioselective synthesis of six-membered nitrogen heterocycles has been the subject of a large number of studies during the past few years due to the interest of these intermediates in natural alkaloid and medicinal chemistry. As a consequence, efficient methods are now available for preparing chiral 2- and 2,6-substituted piperidines.[1] However, few methods are available concerning the corresponding enantiopure substituted tetrahydropyridines.[2] Therefore, we now present a strategy which is briefly summarized in Scheme 1. The main features of this approach are: (a) selective alkylation with Grignard reagents[3–5] of pyridinium salts 1 (Scheme 1), now readily available from chiral primary amines;[6] (b) protonation of the resulting dihydropyridines 2 to give dihydropyridinium salt equivalents 3;[7] (c) additional treatment with a Grignard reagent affording the 2,6-disubstituted tetrahydropyridines 4. Scheme 1. General strategy for the enantioselective construction of substituted tetrahydropyridines The interest of this approach is illustrated by the short synthesis from salt 1c (Scheme 2) of (2)-lupetidin, (1)- solenopsin A and indolizidines (2)-5 and (2)-6, this last synthesis being designed as an example of further ring elaboration of the tetrahydropyridines 4. [a] Institut de Chimie des Substances Naturelles, C.N.R.S. Avenue de la Terrasse, 91198 Gif-Sur-Yvette CEDEX, France Fax: (internat.) 1 33-1/69077247 E-mail: marazano@icsn.cnrs-gif.fr [b] Departamento de Quimica, ICEB, Universidad Federal de Ouro Preto, Campus Morro de Cruzeiro, 35400.00, Ouro Preto, MG, Brazil Eur. J. Org. Chem. 2000, 139121399 Ó WILEY-VCH VerlagGmbH, D-69451Weinheim, 2000 14342193X/00/040821391 $ 17.501.50/0 1391 ine intermediates 11b cyclize to give the new oxazolidine derivatives 12a–e, which turn out to be good precursors of the 2,6-trans-disubstituted tetrahydropyridines 21a–e. Selective syntheses of (–)-lupetidin, (+)-solenopsin, and indolizidines (–)-5 and (–)-6 are presented as representative examples of applications.

Keywords

Alkaloids, Alkylations, Asymmetric synthesis, Grignard reactions

Citation

BERTIN, B. G. et al. Stereocontrolled alkylation of chiral pyridinium salt toward a short enantioselective access to 2-alkyl- and 2,6-dialkyl-1,2,5,6-tetrahydropyridines. European Journal of Organic Chemistry, Alemanha, v. 1, p. 1391-1399, 2000. Disponível em: <http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1099-0690(200004)2000:8%3C1391::AID-EJOC1391%3E3.0.CO;2-D/abstract>. Acesso em: 20 mai. 2017.